Combination lurbinectedin and doxorubicin versus physician's choice of chemotherapy in patients with relapsed small-cell lung cancer (ATLANTIS): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND

Lurbinectedin is a synthetic marine-derived anticancer agent that acts as a selective inhibitor of oncogenic transcription. Lurbinectedin monotherapy (3·2 mg/m

METHODS

In this phase 3, open-label, randomised study, adult patients aged 18 years or older with SCLC who relapsed after platinum-based chemotherapy were recruited from 135 hospitals across North America, South America, Europe, and the Middle East. Patients were randomly assigned (1:1) centrally by dynamic allocation to intravenous lurbinectedin 2·0 mg/m

FINDINGS

Between Aug 30, 2016, and Aug 20, 2018, 613 patients were randomly assigned to lurbinectedin plus doxorubicin (n=307) or control (topotecan, n=127; CAV, n=179) and comprised the intention-to-treat population; safety endpoints were assessed in patients who had received any partial or complete study treatment infusions (lurbinectedin plus doxorubicin, n=303; control, n=289). After a median follow-up of 24·1 months (95% CI 21·7-26·3), 303 patients in the lurbinectedin plus doxorubicin group and 289 patients in the control group had discontinued study treatment; progressive disease was the most common reason for discontinuation (213 [70%] patients in the lurbinectedin plus doxorubicin group vs 152 [53%] in the control group). Median overall survival was 8·6 months (95% CI 7·1-9·4) in the lurbinectedin plus doxorubicin group versus 7·6 months (6·6-8·2) in the control group (stratified log-rank p=0·90; hazard ratio 0·97 [95% CI 0·82-1·15], p=0·70). 12 patients died because of treatment-related adverse events: two (<1%) of 303 in the lurbinectedin plus doxorubicin group and ten (3%) of 289 in the control group. 296 (98%) of 303 patients in the lurbinectedin plus doxorubicin group had treatment-emergent adverse events compared with 284 (98%) of 289 patients in the control group; treatment-related adverse events occurred in 268 (88%) patients in the lurbinectedin plus doxorubicin group and 266 (92%) patients in the control group. Grade 3 or worse haematological adverse events were less frequent in the lurbinectedin plus doxorubicin group than the control group (anaemia, 57 [19%] of 302 patients in the lurbinectedin plus doxorubicin group vs 110 [38%] of 288 in the control group; neutropenia, 112 [37%] vs 200 [69%]; thrombocytopenia, 42 [14%] vs 90 [31%]). The frequency of treatment-related adverse events leading to treatment discontinuation was lower in the lurbinectedin plus doxorubicin group than in the control group (26 [9%] of 303 patients in the lurbinectedin plus doxorubicin group vs 47 [16%] of 289 in the control group).

INTERPRETATION

Combination therapy with lurbinectedin plus doxorubicin did not improve overall survival versus control in patients with relapsed SCLC. However, lurbinectedin plus doxorubicin showed a favourable haematological safety profile compared with control.

FUNDING

PharmaMar.

Informations de copyright

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Déclaration de conflit d'intérêts

Declaration of interests SPA has received honoraria from Roche and Bristol Myers Squibb; has received support for attending meetings or travel from Roche; and has a patent for lurbinectedin plus atezolizumab. TEC reports consultant or advisory fees from Astellas Pharma, Janssen, Bristol Myers Squibb, Merck Serono, Amgen, Roche, Pfizer, Boehringer Ingelheim, Eli Lilly, AstraZeneca, Merck Sharp & Dohme, Sanofi, Novartis, Servier, and A&D Pharma; and travel support from Pfizer, Sanofi, Boehringer Ingelheim, Merck, Servier, Ipsen, Amgen, A&D Pharma, AstraZeneca, Genentech, Bristol Myers Squibb, Merck Sharp & Dohme Oncology, Eli Lilly, Janssen, Novartis, and Astellas Pharma. LB reports payment or honoraria from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, and Roche; and participation on a data safety monitoring board or advisory board for AstraZeneca and Roche. EFS reports consulting fees paid to his institution from Merck and Eli Lilly; payment or honoraria to his institution from Boehringer Ingelheim, AstraZeneca, and Daiichi Sankyo; and participation on a data safety monitoring board or advisory board for Merck, AstraZeneca, and Merck Sharp & Dohme. AC reports payment or honoraria from Genentech, Takeda, Blueprint Medicines, and Amgen; participation on a data safety monitoring board or advisory board for Ipsen, Odonate Therapeutics, Jazz Pharmaceuticals, Aileron Therapeutics, Janssen, AstraZeneca, and Sanofi; and holds stock or stock options in Merck. IH reports personal payments and payments to her institution from Syneos Health UK. AFF reports a consultancy or advisory role with AstraZeneca, Syros, OncLive, Clinical Care Oncology, Bayer, H3 Biomedicine, Pfizer, Medscape, PeerView, Genentech, Merck, Bristol Myers Squibb, and Boehringer Ingelheim; research funding to her institution from Bayer, Genentech, and AstraZeneca; was an employee and held stock or stock options in Novartis; and received support for this manuscript from PharmaMar. JAL-V, ANi, NV, JG, CK, and AZ are employees of PharmaMar and report stock or stock options in PharmaMar. MC-Y is an employee of PharmaMar. KS reports personal consulting fees from Roche, Bristol Myers Squibb, and Merck Sharp & Dohme; and consulting fees paid to his institution from Amgen. IB reports payment or honoraria from AstraZeneca, Amgen, Takeda, Bristol Myers Squibb, and Pfizer. CFW reports consulting fees from Viatris, Roche, and Alvotech; honoraria for lectures from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda; meeting or travel support from Bristol Myers Squibb; and honoraria for advisory boards from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, and Merck Sharp & Dohme. OJ-V reports consulting fees from Boehringer Ingelheim, Merck Sharp & Dohme, AstraZeneca, Eli Lilly, and Takeda; payment or honoraria from Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharp & Dohme, Roche, AstraZeneca, and Takeda; and meeting or travel support from Merck Sharp & Dohme and Roche. NR reports payment or honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Hoffmann-La Roche, Eli Lilly, Merck Sharp & Dohme, Merck, Pfizer, and Takeda; and meeting or travel support from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Hoffmann-La Roche, Merck Sharp & Dohme, Pfizer, and Takeda. MD reports payment or honoraria for lectures and advisory boards from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Sanofi, and Roche. LP-A reports honoraria for scientific advice and speaker fees from Eli Lilly, Merck Sharp & Dohme, Bristol Myers Squibb, Roche, PharmaMar, Merck, AstraZeneca, Novartis, Servier, Amgen, Pfizer, Ipsen, Sanofi, Bayer, Mirati, GlaxoSmithKline, Janssen, and Takeda; participates as external member of the board of Genómica; is a founder and board member of Altum sequencing; and has received institutional support for contracted research from Merck Sharp & Dohme, Bristol Myers Squibb, AstraZeneca, and Pfizer. All other authors declare no competing interests.